It is known that various lipid mediators such as eicosanoid and platelet activating factor (PAF) are produced by the activity of phospholipase from cell membranes.
Lysophosphatidic acid represented by formula (I)
(wherein R is acyl, alkenyl or alkyl) is a lipid which is produced from cell membranes, acts as a mediator in the signal transduction system and delivers various signals into cells. LPA that exists naturally is L-α-LPA.
Recently, the existence of three subtypes of the LPA receptor has been disclosed and it is gradually proved that their physiological activities are via the LPA receptor. Three subtypes of the LPA receptor are called EDG (Endothelial differentiation gene)-2, 4 and 7, respectively, and form a part of EDG receptor family as well as EDG-1, 3, 5, 6 and 8 that are sphingosine-1-phosphate receptor. EDG-2 is called LPA1 or VZG-1, too (Mol Pharmacol, Dec; 58(6): 1188-96 (2000)). The LPA receptor to which LPA binds delivers signals into cells via a G-protein coupled receptor. Gs, Gi, Gq are known as G-proteins that can bind to the LPA receptor, and the receptors are considered to relate to the response to the action of increase or, adversely, decrease of cell growth. Furthermore, since MAP-kinase systems operate in the lower G-protein, it has been known that LPA receptors deliver various signals.
Since LPA receptors exist locally by their subtypes although they exist widely in the organs, it is thought that the role of each receptor is different by the organ.
On the other hand, LPAs which are ligand for LPA receptors have various variants, and three LPAs which are alkenyl type, acyl type or alkyl type, respectively, are known. Furthermore, it is confirmed that each LPA type has the diversity of molecule by the difference of number of unsaturated bond in fatty acid.
The increase of blood pressure in rats, and the contraction of colon in rats and ileum in guinea pigs have been known as the pharmacological activity caused by LPA (J. Pharm. Pharmacol., 43, 774 (1991), J. Pharm. Pharmacol., 34, 514 (1982)). 1-Linolenoyl lysophosphatidic acid ((18:3)-LPA; in formula (I), the compound in which R is CH3(CH2CH═CH)3(CH2)7CO) has the most potent activity for the contraction of colon and ileum in rats by LPA. It is confirmed that 1-linoleoyl lysophosphatidic acid ((18:2)-LPA; in formula (I), the compound in which R is CH3(CH2CH═CH)2(CH2)7CO) and 1-palmitoyl lysophosphatidic acid ((16:0)-LPA; in formula (I), the compound in which R is CH3 (CH2)14CO) also have the activity. However, the contraction caused by phosphatidic acid represented by formula (II):
(wherein R is acyl, alkenyl or alkyl) has been also reported and it has not been examined whether the contraction is occurred by the activity via receptor or not. Furthermore, it has not been examined whether LPA has the pharmacological activity in vivo.
It has been reported that LPA has the contractile activity in the isolated bladder smooth muscle cell (J. Urol., 162, 1779 (1999)), however, it has never been known that LPA relates to the contraction of urethra.
As the relationship between LPA and prostate function, it has been known that LPA increases growth of the epithelial cell derived from prostate (J. Urol., 163, 1027 (2000)). However, it has never been known LPA relates to the contraction of prostate.
The physiologically active substance such as noradrenaline and endothelin are known as substances which cause the contraction of urethra and prostate, and it is known that they active via the each receptor. Therefore, agonists or antagonists of their receptors are used to various diseases which relate to the contraction of urethra. For example, in case of noradrenaline, since α1 receptors are found in urethra, tamsulosin and prazosin which are α1 antagonists decrease the pressure of urethra and are used for the treatment of dysuria according to benign prostatic hyperplasia. On the other hand, since α1 agonists increase the contraction of urethra, they are used for the treatment of urinary incontinence.
Under these background, the contractile activity of urethra and prostate by LPA has never been reported.
In the specification of WO01/60819, it is described that a compound with antagonistic activity for LPA receptor inhibits the activation of cell caused by LPA and is used for the prevention and treatment of diseases such as restenosis after percutaneous transluminal coronary angioplasty (PTCA), arterial sclerosis, malignant and benign proliferative disease, various inflammatory diseases, renal disease, the suppression of growth tumor cell, the invasion and metastasis of cancer, the cerebral or neuropathy. However, it has never been described that it relates to urinary diseases.